Pseudomyxoma peritonei (PMP) and peritoneal carcinomatosis (PC) are rare diseases with an estimated incidence of 1-2 per million per year worldwide. PC affects 15% of all colorectal cancer patients at initial presentation with devastating effects (Coccolini et al, 2013, World J Gastroenterol, 19:6979-6994). These patients typically have a very poor prognosis and suffer from numerous complications of their disease, including progressive bowel obstruction. Optimal treatment involves cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) which has been used with modest success in highly selected patients with limited disease burdens. During CRS-HIPEC, all visible intraperitoneal tumor is debulked and residual microscopic disease is treated with regionally delivered chemotherapy. CRS-HIPEC is most effective when the tumor burden is small following CRS to eliminate any tumor nodules larger than 2.5 mm. Outcomes are dependent on tumor grade, with 5-year survival rates of 63-100% for low grade, and 0%-65% for high grade disease (Sugarbaker et al., 1999, Ann Surg Oncol, 6:727-731). A randomized controlled trial demonstrated that CRS-HIPEC for patients with colorectal cancer PC resulted in significantly improved survival compared to systemic chemotherapy (Verwaal et al., 2003, J Clin Oncol, 21:3737-3743, Verwaal et al., 2008, Ann Surg Oncol, 15:2426-2432). Unfortunately, most PC patients are not candidates for CRS-HIPEC and ultimately progress and die of disease (Coccolini et al, 2013, World J Gastroenterol, 19:6979-6994; Cao et al., 2009, Ann Surg Oncol, 16:2152-2165). Even so, results with CRS-HIPEC for PC suggest that regionally delivered therapeutics are a promising approach to address this large unmet clinical need.
Immunotherapy for advanced solid tumors has gained considerable traction in recent years (Hodi et al., 2010, N Engl J Med, 363:711-723; Kantoff et al., 2010, N Engl J Med, 363:411-422; Khan et al., 2014, J Surg Res, 191:189-195; Saied et al., 2014, J Surg Res, 187:525-535). Several types of immunotherapy exist, including vaccines, antibodies, and immune cell infusions. Cellular immunotherapy for solid tumors has advanced largely through application of chimeric antigen receptor T cells (CAR-Ts). CAR-Ts are of particular interest based in part on their broad applicability since they can be produced for almost any patient and are not restricted by major histocompatibility complex types (Eshhar, 2010, Curr Opin Mol Ther, 12:55-63).
CAR-T targeting carcinoembryonic antigen (CEA) was recently tested in Phase I Hepatic Immunotherapy for Metastases (HITM) clinical trials (NCT01373047, NCT02416466) examining the safety and clinical activity of these cells against colorectal cancer LM (Katz et al., 2015, Clin Cancer Res, 21:3149-3159). As the peritoneal cavity is another common site of failure in stage IV CRC patients, it was worthwhile to test regional CAR-T delivery for PC. While regional delivery may enhance the anti-tumor efficacy of CAR-Ts, intratumoral immunosuppression will likely present additional challenges. The metastatic solid tumor microenvironment contains many immunosuppressive cell types that inhibit CAR-Ts, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) (Kershaw et al., 2013, Nat Rev Cancer, 13:525-541). It has been previously shown that MDSC suppress CAR-T cells, and inhibit the antigen presentation functions of liver B cells (Thorn et al., 2014, J Leukoc Biol, 96:883-894). MDSC accomplish this immunosuppressive function through the PD-1/PD-L1 axis and IDO (Burga et al., 2015, Cancer Immunol Immunother, 64:817-829). Treg are also well studied in tumor microenvironments and have been shown to suppress CAR-Ts via PD-L1 and CTLA4 (Lee et al., 2011, Cancer Res, 71:2871-2881).
Accordingly, provided herein is a method for infusing immunoresponsive cells expressing chimeric T cell receptors to treat subjects diagnosed with PMP/PC. Data are provided which indicate that these genetically programed cells attack tumors expressing specific antigens, such as antigens expressed or specifically expressed on adenocarcinoma cells present in PMP or PC. Moreover, the data support the idea that effective IP CAR-T therapy for PC will be further enhanced through inhibition of immunosuppressive cell populations.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.